经肝动脉化疗栓塞术联合抗血管生成药基础上使用程序性死亡受体1抑制剂治疗中晚期肝细胞癌的有效性和安全性分析

丁晓鹏; 帖君; 余嘉豪; 任鹏伟; 宣国云; 马硕怡; 郭长存; 韩英; 周新民

doi:10.3969/j.issn.1001-5256.2022.05.021

经肝动脉化疗栓塞术联合抗血管生成药基础上使用程序性死亡受体1抑制剂治疗中晚期肝细胞癌的有效性和安全性分析

DOI: 10.3969/j.issn.1001-5256.2022.05.021

空军军医大学第一附属医院消化内科，西安 710032

基金项目:

国家自然科学基金面上项目 (81870421)

伦理学声明：本研究方案于2017年3月13日通过空军军医大学第一附属医院医学伦理委员会审批通过，批号：KY20173351-1号。所有入组患者均知情同意。

利益冲突声明：本研究不存在研究者、伦理委员会成员、受试者监护人以及与公开研究成果有关的利益冲突。

作者贡献声明：丁晓鹏负责研究实施，分析资料，撰写论文；帖君负责CT检查结果判读，评价治疗疗效，拟定写作思路，修改论文；余嘉豪、任鹏伟、宣国云、马硕怡参与论文修改；郭长存、韩英负责课题设计及指导；周新民负责指导写作思路，指导撰写文章并最后定稿。

详细信息

通信作者:
周新民, zhouxmm@fmmu.edu.cn

丁晓鹏、帖君对本文贡献等同, 同为第一作者

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出版历程
- 收稿日期: 2021-09-13
- 录用日期: 2021-10-20
- 出版日期: 2022-05-20

Efficacy and safety of programmed death-1 inhibitor combined with transarterial chemoembolization and anti-angiogenic drugs in treatment of advanced hepatocellular carcinoma

Department of Gastroenterology, The First Affiliated Hospital of Air Force Medical University, Xi'an 710032, China

Research funding:

National Natural Science Foundation of China(Geraral Program) (81870421)

More Information

Corresponding author: ZHOU Xinmin, zhouxmm@fmmu.edu.cn(ORCID: 0000-0002-6521-9885)

摘要

摘要: 目的探讨经肝动脉化疗栓塞术(TACE)联合抗血管生成药(TKI)的基础上后续使用程序性死亡受体1(PD-1)抑制剂与TACE+TKI两种方式治疗中晚期肝细胞癌(HCC)的有效性、安全性和预后影响因素。方法选取2018年6月—2021年7月在空军军医大学第一附属医院所有接受TACE+TKI+PD-1抑制剂和部分接受TACE+TKI治疗的患者。收集患者的临床资料，采用倾向性评分匹配法平衡组间基线特征。计数资料2组间比较采用χ²检验，TACE次数2组间比较采用Wilcoxon秩和检验，Kaplan-Meier法分析患者的总生存期，单因素和多因素Cox回归模型分析相关预后影响因素。结果共筛选到181例中晚期HCC患者，其中TACE+TKI+PD-1抑制剂治疗的患者为50例，倾向性评分匹配后，纳入40例TACE+TKI+PD-1抑制剂治疗患者(观察组)和40例TACE+TKI治疗患者(对照组)。至随访截止时间，中位随访时间为28.6个月(95%CI：22.1~35.1)，观察组的中位生存期为15.9个月(95%CI：7.5~24.2)，对照组中位生存期为11.2个月(95%CI：5.0~17.5)。Cox回归分析提示PD-1抑制剂的应用(HR=0.42，95%CI：0.23~0.80，P=0.008)、TACE次数(HR=0.67，95%CI：0.46~0.99，P=0.043)、Child-Pugh分级(HR=2.40，95%CI：1.15~5.00，P=0.019)和血管侵犯(HR=3.42，95%CI：1.11~9.42，P=0.031)是患者预后的独立影响因素。观察组与对照组的2级以上不良反应发生率均为40%，未见显著性差异(P=0.818)。结论 TACE+TKI+PD-1抑制剂较TACE+TKI治疗中晚期HCC患者可以明显延长患者生存期，且不良反应相对可控。
- 癌, 肝细胞 /
- 化学栓塞, 治疗性 /
- 程序性细胞死亡受体1 /
- 治疗结果
Abstract: Objective To investigate the efficacy and safety of programmed death receptor-1 (PD-1) inhibitor combined with transarterial chemoembolization (TACE) and anti-angiogenic drug tyrosine kinase inhibitor (TKI) versus TACE combined with TKI in the treatment of advanced hepatocellular carcinoma (HCC) and related influencing factors for prognosis. Methods An analysis was performed for all patients who received TACE+TKI+PD-1 inhibitor and some patients who received TACE+TKI in The First Affiliated Hospital of Air Force Medical University from June 2018 to July 2021. Related clinical data were collected, and propensity score matching (PSM) was used to balance the baseline characteristics between groups. The chi-square test was used for comparison of categorical data between two groups; the Wilcoxon rank-sum test was used for comparison of the number of TACE procedures between two groups; the Kaplan-Meier method was used to analyze overall survival (OS), and univariate and multivariate Cox regression models were used to analyze the influencing factors for prognosis. Results A total of 181 patients with advanced HCC were screened out, among whom 50 patients were treated with TACE+TKI+PD-1 inhibitor; after PSM, 40 patients treated with TACE+TKI+PD-1 inhibitor were enrolled as observation group and 40 patients treated with TACE+TKI were enrolled as control group. At the end of follow-up, the median follow-up time was 28.6 (95% confidence interval [CI]: 22.1-35.1) months, and the median OS was 15.9 (95%CI: 7.5-24.2) months in the observation group and 11.2 (95%CI: 5.0-17.5) months in the control group. The Cox regression analysis showed that the application of PD-1 inhibitor (hazard ratio [HR]=0.42, 95%CI: 0.23-0.80, P=0.008), the number of TACE procedures (HR=0.67, 95%CI: 0.46-0.99, P=0.043), Child-Pugh class (HR=2.40, 95%CI: 1.15-5.00, P=0.019), and vascular invasion (HR=3.42, 95%CI: 1.11-9.42, P=0.031) were independent influencing factors for prognosis. The incidence rate of grade > 2 adverse events was 40% for both the observation group and the control group, and there was no significant difference between the two groups (P=0.818). Conclusion Compared with TACE+TKI, TACE+TKI+PD-1 inhibitor can significantly prolong the OS of patients in advanced HCC, with relatively controllable adverse events.
- Carcinoma, Hepatocellular /
- Chemoembolization, Therapeutic /
- Programmed Cell Death 1 Receptor /
- Treatment Outcome

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图 1 两组患者Kaplan-Meier生存曲线

Figure 1. Outcome comparison between observation and control groups in the whole cohort according to Kaplan-Meier method

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图 2 PD-1抑制剂使用的早晚对总生存期的影响

Figure 2. The influence of PD-1 inhibitors on overall survival time between first, second and third line

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图 3 PD-1抑制剂的种类对总生存时间的影响

Figure 3. Effects of different types of PD-1 inhibitors on overall survival time

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表 1 患者基线资料

Table 1. Baseline characteristics for the study patients

临床特征	PSM (1∶1匹配)前				PSM(1∶1匹配)后
临床特征	总计 (n=139)	对照组 (n=89)	观察组 (n=50)	P值	总计 (n=80)	对照组 (n=40)	观察组 (n=40)	P值
男[例(%)]	112(80.6)	72(80.9)	40(80.0)	0.898	63(78.8)	31(77.5)	32(80.0)	＞0.05
年龄＞60岁[例(%)]	46(33.1)	29(32.6)	17(34.0)	0.865	26(32.5)	13(32.5)	13(32.5)	1.000
病因[例(%)]				0.268				0.465
乙型肝炎	119(85.6)	78(87.6)	41(82.0)		69(86.2)	36(90.0)	33(82.5)
丙型肝炎	5(3.6)	4(4.5)	1(2.0)		1(1.2)	0	1(2.5)
其他	15(10.8)	7(7.9)	8(16.0)		10(12.5)	4(10.0)	6(15.0)
靶向药物类型[例(%)]				0.971				＞0.05
索拉非尼或仑伐替尼	104(74.8)	66(74.2)	38(76.0)		59(73.8)	30(75.0)	29(72.5)
阿帕替尼或瑞戈非尼	35(25.2)	23(25.8)	12(24.0)		21(26.2)	10(25.0)	11(27.5)
Child-Pugh评分[例(%)]				0.898				0.780
A级	112(80.6)	72(80.9)	40(80.0)		64(80.0)	31(77.5)	33(82.5)
B级	27(19.4)	17(19.1)	10(20.0)		16(20.0)	9(22.5)	7(17.5)
ECOG评分[例(%)]				0.949				0.789
0分	108(77.7)	69(77.5)	39(78.0)		62(77.5)	32(80.0)	30(75.0)
1分	31(22.3)	20(22.5)	11(22.0)		18(22.5)	8(20.0)	10(25.0)
BCLC分期[例(%)]				0.961				＞0.05
B期	58(41.7)	37(41.6)	21(42.0)		31(38.7)	15(37.5)	16(40.0)
C期	81(58.3)	52(58.4)	29(58.0)		49(61.3)	25(62.5)	24(60.0)
AFP[例(%)]				0.856				0.819
≤400 ng/mL	57(41.0)	37(41.6)	20(40.0)		32(40.0)	15(37.5)	17(42.5)
＞400 ng/mL	82(59.0)	52(58.4)	30(60.0)		48(60.0)	25(62.5)	23(57.5)
腹水[例(%)]				0.767				＞0.05
无	115(82.7)	73(82.0)	42(84.0)		65(81.2)	32(80.0)	33(82.5)
少量	24(17.3)	16(18.0)	8(16.0)		15(18.8)	8(20.0)	7(17.5)
肝外转移[例(%)]				0.236				0.823
无	76(54.7)	52(58.4)	24(48.0)		38(47.5)	20(50.0)	18(45.0)
有	63(45.3)	37(41.6)	26(52.0)		42(52.5)	20(50.0)	22(55.0)
血管侵犯[例(%)]				0.683				0.817
无	92(66.2)	60(67.4)	32(64.0)		50(62.5)	24(60.0)	26(65.0)
有	47(33.8)	29(32.6)	18(36.0)		30(37.5)	16(40.0)	14(35.0)
Up-to-7标准[例(%)]				0.208				0.482
未超出	57(41.0)	40(44.9)	17(34.0)		28(35.0)	16(40.0)	12(30.0)
超出	82(59.0)	49(55.1)	33(66.0)		52(65.0)	24(60.0)	28(70.0)
TACE次数				0.038				0.765
1次	78	55	23		42	20	22
2次	33	21	12		19	10	9
3次	14	6	8		11	7	4
≥4次	14	7	7		8	3	5

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表 2 单因素与多因素分析预后影响因素

Table 2. Univariate and multivariate analysis to explore prognostic factors

临床特征	单因素分析		多因素分析
临床特征	HR(95%CI)	P值	HR(95%CI)	P值
应用PD-1抑制剂(ref: 未应用)	0.47(0.26~0.87)	0.017	0.42(0.23~0.80)	0.008
男(ref: 女)	1.21(0.59~2.50)	0.602
年龄＞60岁(ref: ≤60岁)	1.27(0.69~2.32)	0.441
病因
乙型肝炎(ref: 其他)	3 007.25(0~2.64×10⁸⁷)	0.935
丙型肝炎(ref: 其他)	3 060.73(0~2.68×10⁸⁷)	0.935
索拉非尼和仑伐替尼(ref: 阿帕替尼和瑞戈非尼)	0.84(0.43~1.67)	0.636
Child-Pugh C级(ref: B级)	2.42(1.36~4.70)	0.008	2.40(1.15~5.00)	0.019
ECOG 1分(ref: 0分)	1.41(0.71~2.78)	0.323
BCLC C期(ref: B期)	2.07(1.09~3.91)	0.026	0.85(0.29~2.53)	0.769
AFP＞400 ng/mL(ref: ≤400)	1.02(0.57~1.83)	0.952
腹水(ref: 无)	1.88(0.95~3.72)	0.069
肝外转移(ref: 无)	1.82(1.01~3.27)	0.045	0.73(0.21~2.53)	0.617
血管侵犯(ref: 无)	2.30(1.30~4.07)	0.004	3.24(1.11~9.42)	0.031
超过Up-to-7标准(ref: 否)	1.31(0.73~2.38)	0.368
TACE次数每增加1次	0.64(0.46~0.87)	0.005	0.67(0.46~0.99)	0.043

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表 3 不良反应情况

Table 3. Adverse events

不良反应	观察组(n=40)			对照组(n=40)
不良反应	所有级别	3级	4级	所有级别	3级	4级
乏力[例(%)]	23(57.5)	1(2.5)	0	24(60.0)	3(7.5)	0
腹泻[例(%)]	23(57.5)	2(5.0)	0	20(50.0)	2(5.0)	0
发热[例(%)]	14(35.0)	1(2.5)	0	11(27.5)	2(5.0)	0
高血压[例(%)]	13(32.5)	3(7.5)	0	17(42.5)	3(7.5)	0
手足皮肤反应[例(%)]	11(27.5)	4(10.0)	1(2.5)	15(37.5)	4(10.0)	1(2.5)
皮疹[例(%)]	3(7.5)	2(5.0)	0	3(7.5)	1(2.5)	0
甲状腺功能减退[例(%)]	3(7.5)	1(2.5)	0	1(2.5)	0	0
免疫性肺炎[例(%)]	1(2.5)	0	1(2.5)	0	0	0

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